[ Back to EurekAlert! ] Public release date: 2-Jan-2008
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Journal of Clinical Investigation

JCI online early table of contents: Jan. 2, 2008

EDITOR'S PICK

Il-22 gene delivers the goods and decreases intestinal inflammation

There are two major types of inflammatory bowel disease (IBD), Crohn disease (CD) and ulcerative colitis (UC). Conflicting reports have indicated that the soluble factor IL-22 can have both IBD promoting and IBD controlling effects. But now, Atsushi Mizoguchi and colleagues at Massachusetts General Hospital, Boston, have established that IL-22 ameliorates disease in a mouse model of UC.

Expression of IL-22 is much higher in the intestines of individuals with CD than UC. To investigate the role of IL-22 in IBD, the authors used a new microinjection-based strategy to deliver the gene that makes IL-22 to the walls of the intestine of mice who suffer from an intestinal disease that models UC. Delivery of the Il-22 gene ameliorated local intestinal inflammation through enhanced mucus production. Consistent with this, when the same strategy was used to deliver a gene that makes a protein that neutralizes IL-22, IL-22–binding protein, to the walls of the intestines of normal mice it enhanced chemical-induced intestinal inflammation. The authors therefore suggest that individuals with UC might benefit from local delivery of the IL-22 gene to their intestines.

TITLE: IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis

AUTHOR CONTACT:
Atsushi Mizoguchi
Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 726-2588; Fax: (617) 726-2365; E-mail: amizoguchi@partners.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33194


EDITOR'S PICK

Epilepsy and brain pathology linked together by the protein ADK

The brain of individuals who suffer from epilepsy is characterized by astrogliosis, a brain pathology evidenced by a complex series of changes in the morphology and function of brain cells known as astrocytes. Little is known about how astrogliosis relates to the dysfunction of brain cells known as neurons in individuals with epilepsy, but filling in the blanks in our knowledge could lead to new possibilities for therapeutic intervention. A study using mice by Detlev Boison and colleagues at Legacy Clinical Research, Portland, has now identified the protein ADK in astrocytes as a molecular link between astrogliosis and neuronal dysfunction in epilepsy.

The authors observed in a mouse model of epilepsy that ADK upregulation and spontaneous seizures occurred in the region of the brain affected by astrogliosis. In addition, overexpression of ADK in a specific region of the brain triggered seizures in the absence of astrogliosis. Conversely, mice engineered to express less ADK in specific regions of the brain were protected from chemical-induced epilepsy. Furthermore, as ADK-deficient ES cell–derived implants protected normal mice from chemical-induced astrogliosis, ADK upregulation, and seizures, it was suggested that ADK-based treatment strategies might provide a new approach for the treatment of individuals with epilepsy.

TITLE: Adenosine kinase is a target for the prediction and prevention of epileptogenesis in mice

AUTHOR CONTACT:
Detlev Boison
Legacy Clinical Research, Portland, Oregon, USA.
Phone: (503) 413-1754; Fax: (503) 413-5465; E-mail: dboison@downeurobiology.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33737


ONCOLOGY

AHRR: Aim Here to taRget canceR

Various genes regulate the development of cancer, including those that enhance and those that suppress tumor formation, oncogenes and tumor suppressor genes, respectively. Because various cancers are associated with the deletion of a particular portion of the genome containing AHRR, scientists believe that a tumor suppressor gene is located in that region. A new study by Enrique Zudaire and his colleagues at the National Cancer Institute, Bethesda, has provided evidence that AHRR has tumor suppressor capabilities in a variety of human cancers.

In the study, AHRR gene expression was found to be decreased in cancerous human tissues from various organs including colon, breast, lung, stomach, cervix, and ovary. Artificial suppression of AHRR gene expression in human lung cancer cells using siRNA technology resulted in enhanced tumor cell proliferation, both in culture and when the cells were transplanted into immunocompromised mice. These AHRR-silenced cells also were protected against a form of cell death known as apoptosis, as well as having enhanced migratory and invasive behavior. Finally, overexpression of AHRR in human lung cancer cells resulted in decreased proliferation. The authors therefore concluded from these data that AHRR is a tumor suppressor gene present in various tissues.

TITLE: The aryl hydrocarbon receptor repressor is a putative tumor suppressor gene in multiple human cancers

AUTHOR CONTACT:
Enrique Zudaire
National Cancer Institute, Bethesda, Maryland, USA.
Phone: (301) 496-8050; Fax: (301) 435-8036; E-mail: zudairee@mail.nih.gov.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30024


BONE BIOLOGY

Softly, softly: Phex gene mutation in mouse bone cells causes rickets

X-linked hypophosphatemia (XLH) is the most common form of inherited rickets, a disease characterized by softening of the bones. It is caused by a mutation in the PHEX gene. Mice with a mutation in the equivalent gene (Phex) are known as Hyp-mice and have similar symptoms to individuals with XLH. PHEX/Phex is expressed not just in bone cells of the osteoblast lineage and there are conflicting reports as to whether defects in cells other than osteoblast lineage cells are involved in the disease that manifests in individuals with XLH and Hyp-mice. However, new data generated by Marc Drezner and colleagues at the University of Wisconsin, Madison, has indicated that mutation of Phex only in osteoblast lineage cells recapitulates the disease observed in Hyp-mice. Indeed, in the study, mice in which all cells had a Phex mutation and mice in which only the osteoblast lineage cells known as osteoblasts and osteocytes had a Phex mutation developed disease that mimicked that observed in Hyp-mice.

TITLE: Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia

AUTHOR CONTACT:
Marc K. Drezner
University of Wisconsin, Madison, Wisconsin, USA.
Phone: (608) 262-9288; Fax: (608) 263-9983; E-mail: mkd@medicine.wisc.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32702


NEUROBIOLOGY

Breaking down the potential molecular mechanisms underlying Parkinson disease

New data generated in vitro and in cultured cell lines and mouse neurons, by Ana Maria Cuervo and colleagues at the Albert Einstein College of Medicine, New York, has shed light on the mechanisms by which the protein alpha-synuclein is degraded in brain cells known as neurons. This has implications for the development of the neurodegenerative disorder Parkinson disease (PD) because altered degradation of alpha-synuclein has been implicated as a key step in the development of the disorder.

In the study, posttranslational modification of alpha-synuclein by processes such as by phosphorylation and nitration was shown to impair degradation of this protein by a mechanism known as chaperone-mediated autophagy (CMA) in isolated lysosomes, cultured dopaminergic cell lines, and cultured mouse neurons. Of relevance to PD, in which most of the neurons lost are dopaminergic neurons of the substantia nigra, dopamine-modified alpha-synuclein was poorly degraded by CMA and blocked the degradation of other proteins by CMA. The authors therefore suggested that dopamine-induced inhibition of alpha-synuclein degradation by CMA increases the vulnerability of dopaminergic neurons to cellular stressors, thereby explaining the selective loss of dopaminergic neurons in individuals with PD.

TITLE: Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy

AUTHOR CONTACT:
Ana Maria Cuervo
Albert Einstein College of Medicine of Yeshiva University, New York, New York, USA.
Phone: (718) 430-2689; Fax: (718) 430-8975; E-mail: amcuervo@aecom.yu.edu.

MEDIA CONTACT:
Karen Gardner
Media Relations Manager
Albert Einstein College of Medicine of Yeshiva University, New York, New York, USA.
Phone: (718) 430-3101; E-mail: kgardner@aecom.yu.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32806


NEUROBIOLOGY

Lidocaine can really get on your nerves: Local anesthetics interact with the ion channel TRVP1 on neurons

Very high concentrations of local anesthetics (LAs), such as lidocaine, are often used clinically for spinal anesthesia and for peripheral region anesthesia. Although neuronal damage and death (neurotoxicity) are well-documented potential side effects of these extreme doses of LAs, the mechanism(s) underlying the neurotoxicity has not been well understood. A new study by Carla Nau and her colleagues at Friedrich-Alexander-University of Erlangen-Nuremberg, Germany, has revealed that lidocaine interacts with neurons through TRVP1, an ion channel that is responsible for activation of the pain-sensing sensory neurons. Lidocaine activated TRVP1 located on both rodent neurons and a human cell line. When applied to either isolated mouse skin or sciatic nerves, lidocaine induced TRVP1-mediated release of the peptide CGRP, a key component in inflammation of the nerves. These data led the authors to conclude that TRVP1 is likely to be a key component of LA-associated neurotoxicity, although further investigations are required to pin-point the role of TRVP1 in LA-induced neurotoxicity.

TITLE: The vanilloid receptor TRPV1 is activated and sensitized by local anesthetics in rodent sensory neurons

AUTHOR CONTACT:
Carla Nau
Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
Phone: +49-9131-85-39154; Fax: +49-9131-85-39161; E-mail: carla.nau@kfa.imed.uni-erlangen.de.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32751


VASCULAR BIOLOGY

Adult multipotent progenitor cells ProViDe hope to patients with peripheral vascular disease

Peripheral vascular disease (PVD) is a disease of the limbs caused by obstruction of the blood vessels. Moderate PVD causes pain when walking, which is known clinically as intermittent claudication (IC); while patients with severe disease have decreased blood and oxygen flow in the limbs (critical limb ischemia [CLI]) that can result in tissue injury or death. Although treatments exist, such as surgically bypassing or opening the obstructed blood vessel, many patients with moderate-to-severe PVD often have underlying disorders that make surgical intervention dangerous. In a new study, Aernout Luttun and colleagues from the Katholieke Universiteit Leuven, Belgium, investigated the potential for multipotent adult progenitor cells (MAPCs) to improve the function of mouse tissues damaged by PVD.

MAPCs are immature cells in an adult organism that give rise to several different cell types, through a process known as differentiation. The authors investigated the effect that two different mouse progenitor cell populations — undifferentiated MAPCs (MAPC-Us) and vascular progenitor cells derived from MAPCs (MAPC-VPs) — had on mice with moderate or severe limb ischemia. When injected into mice with a moderate ischemia similar to IC in humans, mouse MAPC-Us restored blood flow and muscle function, and stimulated muscle regeneration. In contrast, neither mouse MAPC-VPs nor mouse BMCs (bone marrow–derived, non-progenitor cells) caused muscle regeneration. Further analysis revealed that both mouse and human MAPC-Us improved muscle function and restored blood flow in mice with a severe limb ischemia similar to CLI in humans. From these results, the authors concluded that undifferentiated MAPCs might have the potential to repair damage due to vessel obstruction in patients with PVD.

TITLE: Multipotent adult progenitor cells sustain function of ischemic limbs in mice

AUTHOR CONTACT:
Aernout Luttun
Katholieke Universiteit Leuven, Leuven, Belgium.
Phone: 32-16-34-57-72; Fax: 32-16-34-59-90; E-mail: aernout.luttun@med.kuleuven.be.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31153


TRANSPLANTATION

Antibody makes cells mediating transplant rejection TIMid

Recent work has demonstrated that an antibody that binds with low affinity to the protein TIM-1 on the surface of immune cells known as CD4+ T cells protects mice from disease in a mouse model of multiple sclerosis. Now, Mohamed Sayegh and colleagues from Harvard Medical School, Boston, have shown that a short course of this antibody prolongs the survival of nongenetically identical heart transplants (allografts) in mice. If treatment with the TIM-1–specific antibody was combined with subtherapeutic doses of the immunosuppressive drug rapamycin the allografts were not rejected for the length of the study. The mechanisms underlying the effects of the TIM-1–specific antibody were found to involve inhibition of alloreactive Th1 responses and preservation of Th2 responses. In addition, regulatory T cells were also shown to have a central role, as if mice were depleted of these cells prior to transplantation the TIM-1–specific antibody failed to prolong allograft survival. The authors therefore suggested that TIM-1–specific antibody therapy might provide a new approach to preventing transplant rejection.

TITLE: The emerging role of T cell Ig mucin 1 in alloimmune responses in an experimental mouse transplant model

AUTHOR CONTACT:
Mohamed H. Sayegh
Brigham and Women’s Hospital, and Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 732-5259; Fax: (617) 732-5254; E-mail: msayegh@rics.bwh.harvard.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32451


NEPHROLOGY

It is no use sugar coating it: IgA1 is prematurely sialylated in individuals with IgA nephropathy

Among individuals with the relatively common kidney disease IgA nephropathy, 20–40% go on to develop end-stage kidney disease. The disease is characterized by the accumulation of immune complexes in small clusters of capillaries in the kidneys known as glomeruli. The antibodies in these immune complexes are IgA1 molecules whose sugar coatings have not been formed correctly and that are said to be aberrantly glycosylated, that is, the hinge-region O-linked glycans are galactose deficient. In a new study, Jan Novak and colleagues at the University of Alabama at Birmingham, generated IgA1-producing cell lines from the peripheral blood of patients with IgA nephropathy and demonstrated that premature sialylation is likely to contribute to the aberrant IgA1 glycosylation in individuals with this disease. The authors therefore suggested that inhibiting proteins in the biochemical pathway that mediates IgA1 sialylation, such as ST6GalNAcII, might provide a new approach to treating individuals with IgA nephropathy.

TITLE: IgA1-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgA1

AUTHOR CONTACT:
Jan Novak
University of Alabama at Birmingham, Birmingham, Alabama, USA.
Phone: (205) 934-4480; Fax: (205) 934-3894; E-mail: jannovak@uab.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33189

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